The present invention relates to cholanic acid ring based 4-(trifluoroacetyl)phenyl derivatives of the following formula 1, process for preparation thereof and use thereof as host materials in the host-guest chemistry. ##STR2##
In formula 1,
n is a value representing the length of an alkyl chain and is 0-3; PA1 R represents alkyl(C.sub.1 -C.sub.20), alkoxy(C.sub.1 -C.sub.20) methyl, alkoxy(C.sub.1 -C.sub.20) carbonyl, dialkyl(C.sub.1 -C.sub.20) amide, dialkyl (C.sub.1 -C.sub.20) ethylene or diphenylethylene; PA1 R.sup.1 and R.sup.3 represent acetoxy or 4-trifluoroacetyibenzoxy; and PA1 R.sup.2 represents hydrogen, keto, acetoxy or 4-trifluoroacetylbenzoxy.
In the last twenty years there has been extensive development in the supramolecular chemistry, and in recent years supramolecules are applied in various and complex ways.
The supramolecules, obtained from natural sources or synthesized by introduction of various functional groups in a molecule, can be used diversely in the host-guest chemistry. The host-guest chemistry is a field to study the interaction of ions or molecules with a compound having several functional groups or an empty site in the molecule. It has attracted a good deal of attention and has been actively studied since Morf et al. had reported that most of the ionophores in nature, which usually act as antibiotics, tend to transport cations selectively across biomembrane (Helv. Chim. Acta 1971, 54, 268).
The supramolecules in the host-guest chemistry are designed by suitably arranging functional groups stereospecifically to bind a guest molecule selectively, so that it is possible to recognize a guest molecule energetically and/or stereospecifically by intermolecular interactions. The scope of guest molecules is also extended to ion species as well as neutral molecules. The compounds such as crown ethers, podants, cryptands and spherands are used as representative ion-selective hosts which can quantify specific ions in ion-selective electrodes and optical sensors, and as ion-selective membranes acting as signal transducer in biosensors and gas sensors.
The steroid-type molecules can be used as primary skeleton for application to the supramolecular chemistry and the host-guest chemistry in considering the aforesaid size, chirality and multiple ring fixed structurally. In particular, the bile acid-type molecules have been actively studied since those are readily available and it is possible to control the extend of introduction of functional groups. The examples of the above bile acid-type molecules are shown below. ##STR3##
As represented below, the applicability of the above molecules has been studied recently for a host molecule of carbohydrate, wherein a cholaphane having a cavity in a supramolecule was synthesized by connecting the two units of cholic acid, one of bile acids, by two benzyl linkers (A. P. Davis, R. P. Bonar-law, J. Chem. Soc., Chem. Commun., 1989, 1050). ##STR4##
In addition, the host molecules shown below have been reported as molecular tweezers, in which the two pyrene groups were introduced into cholic, ketocholic, and deoxycholic acid esters, and the resultant host molecules can interact with an aromatic molecule (U. Maitra, J. Org. Chem., 1996, 61, 9494). ##STR5##
Cholic acid, one of bile acids, is characterized by containing a rigid steroidal ring structure and having the 3.alpha.-, 7.alpha.- and 12.alpha.-hydroxyl groups arranged nearly perpendicularly to the one side of the ring plane. In considering the proposed mechanism that two molecules of 4-(trifluoroacetyl)phenyl derivatives interact with a carbonate anion as represented below, the above properties have advantages that more than two 4-(trifluoroacetyl)benzoxy groups can be introduced into the one side of the molecule. That is, the binding of a carbonate anion to one 4-(trifluoroacetyl)benzoxy group could enhance the binding of the other 4-(trifluoroacetyl)benzoxy group in the same molecule. ##STR6##
The distances between 3- and 7-, 7- and 12-, and 3- and 12-hydroxyl groups are expected to be 4.9 .ANG., 4.6 .ANG., and 6.2 .ANG., respectively. Since the distances between the two hydroxyl groups are similar to, or a little larger than the size of carbonate anion (4.8 .ANG.), it is expected that compounds with two or more 4-(trifluoroacetyl)benzoxy groups at hydroxyl groups in cholanic acid derivatives can exhibit an excellent property as hosts of carbonate anion.
A representative usage of ionophores is an ion sensor. An ion-selective membrane electrode, one of ion sensors, measures the potential difference generated by a charge separation between layers formed on membrane surface when a specific ion or a molecule binds to ionophores in the ion-selective membrane attached in the electrode. This electrode has advantages of an excellent selectivity for specific ions, a short analysis time and a low cost, and therefore it has been used for measuring ion species in the food chemistry, the fermentation process, the environmental chemistry and the clinical chemistry such as a hemodialysis, a blood electrolyte continuous autoanalysis, and an extracorporeal blood, owing to the development during the last 30 years. In particular, ion-selective membrane electrodes have been successfully applied to analysis of electrolyte ions such as potassium ion, sodium ion, calcium ion, carbonate ion and chloride ion in biological sample analysis by using various neutral carriers, as ionophores, which can bind selectively to specific ions.
An ion-selective membrane electrode can be classified into a conventional ion-selective membrane electrode and a solid-state ion-selective membrane electrode. The former has an inner reference filling solution between an ion-selective membrane and an inner reference metal electrode, and the latter needs not an inner reference filling solution (See FIG. 1a and FIG. 1b).
The general composition of ion-selective membranes attached in the electrode comprises a polymer as a matrix, an ionophore which binds with a specific ion to separate charge and a plasticizer of a non-volatile organic solvent, and may contain lipophilic additives further according to the type of ion-selective membrane.
p-Decyl-.alpha.,.alpha.,.alpha.-trifluoroacetophenone (hereinafter, referred to as "TFADB"), one of 4-(trifluoroacetyl)phenyl derivatives has been most extensively used as an ionophore of carbonate ion-selective membrane electrode. However, there is a limit for the selective detection of carbonate ion because the response to lipophilic anions such as salicylate is higher than to carbonate ion in biological sample analysis (See FIG. 2a). In the case of the serum of patient administered a lot of aspirin, particularly, the interference of salicylate ion is known to be very serious. There have been several studies for removing the interference of salicylate ion, such as the method of inserting an error code to induce the measurement by a different analysis tool in the case of a serious interference of salicylate ion detected and the method of adding anion-binding complexone into buffer solution to precipitate salicylate ion, suggested by Scott et al. (W. J. Scott, E. Chapoteau, A. Kumar, Clin. Chem., 1986, 32, 137). However, these methods are just a pretreatment of sample and cannot remove the interference essentially. Recently, as another method, Lee et al. have developed the method of reducing the interference of salicylate ion by using the asymmetric carbonate ion-selective membrane electrode having a hydrophilic membrane introduced into the carbonate ion-selective membrane (K. S. Lee, J. H. Shin, S. H. Han, G. S. Cha, D. S. Shin, H. D. Kim, Anal. Chem., 1993, 65, 3151). However, the said method also doesn't change the selectivity of carbonate ion-selective membrane and has a disadvantage of difficulty in the construction of a membrane electrode because of a bilayer membrane structure. Therefore in order to remove or reduce the interference of salicylate ion essentially, the ionophore interacting directly with ions in membrane has to be substituted by a material having the excellent selectivity for carbonate ion.
We, the inventors of this invention, have investigated the improvement of ionophores used in an ion-selective membrane electrode and a biosensor, and have synthesized cholanic acid ring based 4-(trifluoroacetyl)phenyl derivatives. These materials can be used as host materials in the host-guest chemistry, and particularly they have an excellent selectivity for carbonate ion, so that the said derivatives can be widely used in -ion sensors, optical sensors, gas sensors, biosensors, chromatographies, photostimulated ion binding resins, ion exchange resins, and organic reactions.